Process for the preparation of substituted phenylboronic acids

ABSTRACT

Compounds of the formula (I)  
                 
 
     in which  
     Q 1  and Q 2  are each OH or form a trimeric boric anhydride,  
     Z is CHO, CH 2 Y, X or a protected aldehyde group, and X is CN, COOH, COCl, CONH 2  or C(OR) 3 , and Y is OH or NH 2 , and Z is in the o-, m- or p-position to the boronic acid radical,  
     are prepared by  
     a) reacting a compound of the formula (II)  
                 
 
      with Mg in the presence of an anthracene compound and, if desired, a transition-metal halide and, if desired, an Mg halide or in the presence of a transition-metal halide and, if desired, an Mg halide, to give the corresponding arylmagnesium chloride,  
     b) reacting the latter with a borate of the formula B(OR′) 3  and hydrolyzing the product, with removal of the aldehyde protecting group,  
     c) and, if desired, oxidizing or reducing the free aldehyde group.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present invention is described in the German priorityapplication No. DE 199 17 979.4, filed Apr. 21, 1999, which is herebyincorporated by reference as is fully disclosed herein.

BACKGROUND OF THE INVENTION

[0002] Substituted phenylboronic acids, for example cyanophenylboronicacids, are of considerable industrial importance as precursors foractive compounds, in particular as precursors for correspondinglysubstituted biphenyl derivatives, which are used as AT(II) antagonists,or as precursors for liquid-crystalline compounds, as liquid crystals oras a constituent of liquid-crystalline mixtures. Phenylboronic acids canbe coupled to haloaromatic compounds with transition-metal catalysis togive biphenyl derivatives with the aid of methods described in theliterature (N. Miyaura et al., Tetrahedron Lett., 3437 (1979); A. L.Casalnuovo et al., J. Amer. Chem. Soc. 112, 4324 (1990), N. Miyaura etal., Chem. Rev. 95 (1995), 2457-2483).

[0003] The conventional synthetic routes for cyanophenylboronic acids,either starting from carboxyphenylboronic acid via the formation of theacid amide with subsequent formation of the cyano compound or startingfrom the correspondingly substituted bromobenzonitrile by reaction withorganolithium compounds, such as butyllithium, followed by reaction witha trialkyl borate, do not achieve the object of an economical synthesisof cyanophenylboronic acids which is simple to carry out industrially,since firstly the synthetic route contains too many steps, and secondly,organolithium compounds are very expensive and hazardous to handle.

[0004] The Grignard reaction with chlorobenzaldehyde proceeds in lowyields and very slowly, meaning that for industrial purposes, it washitherto necessary to use expensive bromobenzaldehyde (H. Jendralla etal., Liebigs Ann. 1995, 1253-1257).

[0005] WO 98/02 443 uses transition-metal compounds, if necessary incombination with co-catalysts, for activating aromatic chlorinecompounds for Grignard reactions, but not for chlorinated aromaticaldehydes or protected derivatives thereof. Rather, it is known thatether and acetal protecting groups considerably reduce the reactivity ofthe magnesium by forming complexes at the magnesium surface (D. E.Pearson et al., J. Org. Chem., 1959, 24, 504-509).

SUMMARY OF THE INVENTION

[0006] Owing to the interest in this class of substances, there is aneed for an economical synthesis of substituted phenylboronic acids, inparticular of cyanophenylboronic acids, which is simple to carry outindustrially.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] This object is achieved by a process for the preparation of acompound of the formula (I)

[0008] in which

[0009] Q¹ and Q² are each OH or together are a divalent radical of theformula (Ib)

[0010] Z is —CHO, D, —CH₂Y or X, where D is a protected aldehyde group,Y is hydroxyl or amino, and X is cyano, COOH, COCl, CONH₂ or C(OR)₃,where R is C₁-C₅-alkyl or phenyl, and where Z is in the ortho-, meta- orpara-position to the boronic acid radical;

[0011] R¹ to R⁴, independently of one another, are hydrogen,C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, C₃-C₁₂-cycloalkyl,(C₁-C₁₂-)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl, fluorine,N(alkyl)₂, N[Si(C₁-C₄-alkyl)₃]₂ or CF₃, or R¹ and R², and/or R³ and R⁴,together form a 5-or 6-membered aliphatic or aromatic ring;

[0012] which comprises

[0013] a) reacting a compound of the formula (II)

[0014]  with magnesium in the presence of

[0015] i) an anthracene compound and, if desired, a transition-metalhalide and, if desired, a magnesium halide; or

[0016] ii) a transition-metal halide and, if desired, a magnesiumhalide, where the anthracene compound is a compound from the groupconsisting of anthracene, Mg anthracene, substituted anthracene andsubstituted Mg anthracene,

[0017] to give an arylmagnesium chloride of the formula (III)

[0018] b) reacting the compound of the formula (III) with a borate ofthe formula B(OR′)₃, in which R′ are identical to or different from oneanother and are straight-chain or branched (C₁-C₈)-alkyl radicals,phenyl radicals which are unsubstituted or substituted by one or two(C₁-C₄)-alkyl groups or (C₁-C₄)-alkoxy groups, in particularstraight-chain or branched (C₁-C₄)-alkyl radicals or unsubstitutedphenyl radicals, and hydrolyzing the product to give a compound of theformula (IV)

[0019] in which

[0020] D¹ is CHO or D;

[0021] Q¹ and Q² are each OH or together are a divalent radical of theformula (IVb)

[0022] c) if desired oxidizing the compound of the formula (IV) or (IVb)in which D¹ is CHO to give a compound of the formula (I) in which Z isX, or if desired reducing the compound of the formula (IV) or (IVb) togive a compound of the formula (I) in which Z is CH₂Y.

[0023] In the above definitions, alkyl is preferably C₁-C₄-alkyl, arylis preferably phenyl, alkylaryl is preferably benzyl, and alkoxy ispreferably C₁-C₄-alkoxy.

[0024] Preferred radicals R (Z is —C(OR)₃) are C₁-C₄-alkyl, inparticular methyl, ethyl or phenyl.

[0025] Preferred radicals R¹ to R⁴ are hydrogen, methyl, ethyl, propyl,butyl, methoxy, ethoxy, propoxy, butoxy and fluorine.

[0026] The radical D is preferably an acetal of the formula (V) or (VI)

[0027] in which R⁵ to R⁸ are identical or different and are hydrogen,C₁-C₁₂-alkyl or phenyl, or R⁶ and R⁷ together form a 5- or 6-memberedaliphatic or aromatic ring; or D is an oxazolidine of the formula (VII)or an oxazoline of the formula (VIII)

[0028] in which R⁵ to R⁸ are as defined above, and R⁹ is C₁-C₆-alkyl,phenyl or benzyl, unsubstituted or substituted on the aromatic ring.

[0029] It was surprising that compounds of the formula (I) can beprepared in good yields by the process according to the inventionstarting from ortho-, meta- or para-chlorobenzaldehyde.

[0030] Preferred borates B(OR′)₃ are trimethyl borate, triethyl borate,tri-n-propyl borate, triisopropyl borate, tri-n-butyl borate andtriisobutyl borate.

[0031] The group D is, if desired, converted into a compound of theformula (I) in which Z is —CHO by acidic hydrolysis or (in the case ofthe oxazolines) by reduction followed by acidic hydrolysis. It is alsopossible to remove the aldehyde protecting group in a one-pot processand, without prior isolation of a compound of the formula (IV) in whichD¹ is D, to obtain a compound of the formula (IV) in which D¹ is —CHO.

[0032] It is likewise possible, by reacting compounds of the formula(IV) with alcohols of the formula HO-(C₁-C₁₂)-alkyl,HO-(C₂-C₁₂)-alkenyl, HO-(C₂-C₁₂)-alkynyl, HO-aryl or HO-alkylaryl, toprepare acyclic boronates of the formula (IVa)

[0033] in which Q³ and Q⁴ are a radical of said alcohols,

[0034] or, by reaction with the polyhydric alcohols(C₃-C₁₂)-cycloalkane-1,2-diol, (C₅-C₁₂)-cycloalkene-1,2-diol,(C₅-C₁₂)-cycloalkane-1,3-diol, (C₅-C₁₂)-cycloalkene-1,3-diol or with thealcohols of the formulae (1) to (6)

[0035] in which R₁a to R₈a, independently of one another, are hydrogen,C₁-C₁₂-alkyl, C₁-C₁₂-hydroxyalkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl,C₃-C₁₂-cycloalkyl, (C₁-C₁₂)-alkoxy, O-phenyl, O-benzyl, aryl,heteroaryl, fluorine, chlorine, NH₂, NH(alkyl), N(alkyl)₂,N[Si(C₁-C₄-alkyl)₃]₂ or CF₃, and/or two adjacent radicals R₁a to R₈atogether form a 5- or 6-membered aliphatic or aromatic ring, and inwhich n is an integer from 2 to 12,

[0036] to prepare a cyclic borate of the formula (IVa) in which Q³ andQ⁴ together are a divalent radical of said polyhydric alcohols.

[0037] The compounds of the formula (IVa) can be converted back intocompounds of the formula (IV) by acidic hydrolysis.

[0038] The compounds of the formula (I) in which Z is CHO, X or —CH₂Ycan likewise be converted into the compounds of the formula (la) byreaction with the above-mentioned alcohols.

[0039] The compounds of the formula (la) can be converted back intocompounds of the formula (I) by acidic hydrolysis.

[0040] The reaction of the compound of the formula (I) or of the formula(IV) with the alcohols on which the radicals Q³ and Q⁴ are based isadvantageously carried out in the presence of an organic solvent whichis inert toward the reaction participants, such as tetrahydrofuran,methyl tert-butyl ether, toluene, o-, m- or p-xylene, hexane or heptane,at a temperature of from 20° C. to the boiling point of the solventused. In the case of diols or other polyhydric alcohols, it is alsopossible to use methanol, ethanol, n- or isopropanol as inert solvent.The diol on which the radicals Q³ and Q⁴ are based is advantageouslyemployed in an equimolar amount, based on the boronic acid.

[0041] Preferred radicals Q³ and Q⁴ are —O-(C₁-C₆)alkyl,—O-(C₂-C₆)alkenyl, —O-(C₃-C₆)-alkynyl, —O-phenyl, —O-benzyl, or Q³ andQ⁴, together with the boron atom, form a cyclic boronate with thealcohols ethylene glycol, 1,2-propanediol, 1,3-propanediol,1,4-butanediol, 2,2-dimethylpropane-1,3-diol, pyrocatechol, pinacol,2,3-dihydroxynaphthalene, 1,2-dihydroxycyclohexane,1,3-dihydroxycyclopentane or 1,2-dihydroxycyclooctane.

[0042] Particularly preferred radicals Q³ and Q⁴, together with theboron atom, form a cyclic boronate with the alcohols ethylene glycol,1,3-propanediol, 2,2-dimethyl-1,3-diol, pinacol and pyrocatechol.

[0043] The trimeric compounds of the formula (Ib) or (IVb) can beprepared from the corresponding monomeric compounds of the formula (I)or (IV) respectively, for example by heating at from 40 to 100° C.,preferably from 50 to 75° C.

[0044] The process according to the invention is shown in Scheme 1below:

[0045] The aldehyde group is firstly converted into amagnesium-unreactive form, for example into a cyclic or a cyclic acetal,preferably ethylene glycol acetal, dimethyl or diethyl acetal, anoxazolidine or an oxazoline.

[0046] Chlorobenzaldehydes can be reacted with 1,2-diols by conventionalmethods to give correspondingly substituted 1,3-dioxolanes of thegeneral formula (V) or with trialkyl ortho-esters, such as trimethylorthoformate, triethyl orthoformate, triisopropyl orthoformate orcorresponding orthoacetates, to give acyclic acetals of the generalformula (VI). Preference is given here to the reactions with ethyleneglycol, pyrocatechol, trimethyl orthoformate, triethyl orthoformate ortriisopropyl orthoformate.

[0047] Chlorobenzaldehydes can be reacted with 1,2-aminoalcohols whichare monosubstituted on the nitrogen to give correspondingly substitutedoxazolidines of the general formula (VII) by azeotropic distillation ofthe water of reaction (T. H. Fife, L. Hagopian, J. Am. Chem. Soc. 1968,1007-1014). Preferred aminoalcohols are N-methyl-2-aminoethanol,N-ethyl-2-aminoethanol, N-propyl-2-aminoethanol, N-butyl-2-aminoethanol,N-phenyl-2-aminoethanol, N-benzyl-2-aminoethanol,N-methyl-2-aminopropanol, N-ethyl-2-aminopropanol,N-propyl-2-aminopropanol, N-butyl-2-aminopropanol, particularlypreferably N-ethyl-2-aminoethanol, N-butyl-2-aminoethanol,N-phenyl-2-aminoethanol, N-benzyl-2-amino-ethanol.

[0048] It is furthermore possible to react the correspondinglysubstituted chlorobenzoyl chloride with 1,2-aminoalcohols by a methoddescribed in J. Org. Chem. 1988, 53, 345-352, to give oxazolines.

[0049] Preference is given here to 2-amino-2-methylpropan-1-ol and2-aminoethanol.

[0050] The compound of the formula (II) is converted in accordance withthe invention into the Grignard compound of the formula (III) using Mgpowder or turnings in the presence of

[0051] i) an anthracene compound or ii) an anthracene compound and atransition-metal halide or iii) an anthracene compound and a magnesiumhalide or iv) an anthracene compound, a transition-metal halide and amagnesium halide or v) a transition-metal halide or vi) atransition-metal halide and a magnesium halide.

[0052] The anthracene compounds employed can be unsubstituted anthraceneor Mg anthracene, substituted, for example by 1 to 4 (C₁-C₄)-alkylgroups or phenyl groups, anthracene or Mg anthracene, in particular9,10-diphenylanthracene or Mg 9,10-diphenylanthracene. The anthracenecompounds can be added in amounts of from 0.5 to 100 mol %, preferablyfrom 1 to 10 mol %, based on the haloaromatic compounds, oralternatively formed in situ.

[0053] The transition-metal halides are preferably chlorides orbromides, in particular FeCl₂, MnCl₂, FeBr₂ or MnBr₂. Thetransition-metal halides can be added in amounts of from 0.5 to 100 mol%, preferably from 1 to 10 mol %, based on the haloaromatic compounds.

[0054] Suitable magnesium halides are MgCl₂ and MgBr₂. They can be addedin amounts of from 0.5 to 100 mol %, preferably from 1 to 10 mol %,based on the haloaromatic compounds.

[0055] The Grignard reaction is preferably carried out at the boilingpoint of the corresponding solvent and under a protective-gasatmosphere. Suitable solvents are usually tetrahydrofuran, diethylether, monoglyme and diglyme and a solution ofN,N,N′,N′-tetramethylethylenediamine in toluene. It may be advantageousbefore commencement of the reaction to activate the magnesium by amethod described in Y.-H. Lai, Synthesis 585-604 (1981) or to carry outthe Grignard reaction in the presence of small amounts, for example from0.01 to 10 mol %, preferably from 0.1 to 1 mol %, based on thehaloaromatic compounds, of a haloalkane, such as, for example,1,2-dibromoethane, bromoethane or iodomethane.

[0056] The compound of the formula (III) is novel and is likewise asubject-matter of the present invention. The compound of the formula(III) can be isolated by removing the solvent by distillation under aprotective-gas atmosphere.

[0057] In order to obtain phenylboronic acids, the compound of theformula (III) is reacted, preferably without interim isolation, with theborate of the formula B(OR′)₃, in particular with B(OCH₃)₃, B(OEt)₃ orB(OiPr)₃, and subsequently hydrolyzed under aqueous conditions to give acompound of the formula (IV). The reaction with the borate isadvantageously carried out at a temperature of from −80° C. to +20° C.,preferably from −50° C. to +10° C., in particular from −25° C. to 0° C.

[0058] The borate is advantageously employed in a 1- to 1.5-fold molaramount, based on the Grignard compound.

[0059] The compound of the formula (IV) can subsequently be hydrolyzedunder acidic conditions, for example using sulfuric acid at pH 0 to 3.If D is an acetal or oxazolidine group, a preferred procedure is, whenthe addition of the borate is complete, to add the reaction mixture toice-water and to set the pH of the suspension to from 1 to 2, forexample using sulfuric acid, giving the compound of the formula (IV) inwhich D¹ is CHO and Q¹ and Q² are each OH.

[0060] Oxazolines, i.e. D is a radical of the formula (VIII), can beconverted into the aldehyde by a method described in J. Am. Chem. Soc.1983, 105, 1586-1590, by alkylation on the nitrogen using alkyl halides,for example methyl iodide, methyl bromide, ethyl iodide or ethylbromide, or using dialkyl sulfates, for example dimethyl sulfate ordiethyl sulfate, hydrogenation using complex metal hydrides, such asLiAlH₄, NaBH₄ or NaBH₃(CN), followed by acidic hydrolysis.

[0061] During the hydrolysis, the aldehyde predicting group is removedand the boronate is converted into the free boronic acid. Theformylphenylboronic acid of the formula (I) in which Z is CHO can beisolated from the organic phase of the reaction mixture.

[0062] Secondary products can be prepared as shown in Scheme 2 byoxidation or reduction of the aldehyde. In this scheme, Q₁₀ and Q₂₀ areQ₁ and Q₂, or Q₃ and Q₄ if the formylphenylboronic acid is esterified,before the oxidation or reduction, by the above-described method usingan alcohol on which the radicals Q₃ and Q₄ are based, in an inertorganic solvent. This is particularly advantageous if oxidation issubsequently carried out.

[0063] a) From formylphenylboronic acid and its borates, thecorresponding cyanophenylboronic acid of the formula (I) in which Z isCN is obtained by reaction with hydroxylamine or hydroxylammonium saltsfollowed by dehydration of the oxime formed. The dehydration can becarried out by heating in glacial acetic acid or in acetic anhydride (J.Chem. Soc. 1933, IX, 43). By a method proposed in EP-A1-0 790 234, thenitrile function is obtained by reaction of the benzaldehyde derivativewith hydroxylamine sulfate in the presence of a tertiary amine base andazeotropic distillation of the water of reaction.

[0064] b) The corresponding carboxyphenylboronic acid of the formula (I)in which Z is COOH can be prepared by oxidation of formylphenylboronicacid using barium permanganate or potassium permanganate, for example inaccordance with U.S. Pat. No. 5,631,364.

[0065] c) The compound of the formula (I) in which Z=CH₂OH can beobtained by reduction using Raney nickel/hydrogen or using complex metalhydrides, such as LiAlH₄ or NaBH₄.

[0066] d) The compound of the formula (I) in which Z=COCl can beobtained by a method described in Ginsburg, D., J. Amer. Chem. Soc.,1951, 73, 702-704, by reaction of formylphenylboronic acid with t-BuOClin carbon tetrachloride.

[0067] Starting from cyanophenylboronic acid or borates, furthersecondary products can be prepared in accordance with Scheme 3.

EXAMPLES

[0068]

[0069] e) Carboxyphenylboronic acids can be obtained by hydrolysis ofcyanophenylboronic acid, for example analogously to M. V. Sargent, J.Chem. Soc. Perkin Trans. 1, 1987 (1), 231.

[0070] f) Carboxamidophenylboronic acids can be prepared by a methoddescribed in Liu, K.-T.; et al., Synthesis 1988 (9), 715, starting fromcyanophenylboronic acid using MnO₂ on silica gel and water in an organicsolvent.

[0071] g) Carboxylic acid orthoester phenylboronic acids can be preparedby a method described in P. Hamann et al., Synthetic Commun. (1989) 19(9-10.), 1509-1518, from cyanophenylboronic acid using the correspondingalcohol ROH with addition of anhydrous hydrogen chloride to give thecorresponding orthoester, in which R can be C₁-C₁₂-alkyl or aryl,preferably methyl, ethyl or phenyl.

[0072] h) Methyleneaminophenylboronic acids can be prepared by a methoddescribed in B. S. Biggs et al., Org. Synth. 1947, 27, by hydrogenationusing hydrogen and Raney nickel as catalyst.

Example 1

[0073] 2.7 g (110 mmol) of magnesium turnings were added to a solutionof 2 g (11 mmol) of anthracene in 100 ml of THF, and a few drops of1,2-dibromoethane were added. After the mixture had been stirred at roomtemperature for about 2 hours, the bright orange precipitate ofmagnesium anthracene had formed. A solution of 19 g (100 mmol) of4-chlorobenzaldehyde dimethyl acetal in 100 ml of THF was added to therefluxing suspension over the course of 1 hour. After the mixture hadrefluxed for 4 hours, the yield of Mg 4-chlorobenzaldehyde dimethylacetal according to GC analysis (determined as benzaldehyde afterhydrolysis using dilute HCl) was 90%.

Example 2

[0074] 100 ml of THF, 1.18 g (5.5 mmol) of anhydrous iron(II) bromide,1.01 g (5.5 mmol) of magnesium bromide and a few drops of dibromoethanewere added to 2.7 g (110 mmol) of magnesium turnings. After the mixturehad been stirred at room temperature for about 2 hours, the mixture hadbecome a dark-brown to black color. A solution of 19 g (100 mmol) of4-chlorobenzaldehyde dimethyl acetal in 100 ml of THF was added to therefluxing suspension over the course of 1 hour. After the mixture hadrefluxed for 4 hours, the yield of Mg 4-chlorobenzaldehyde dimethylacetal according to GC analysis (determined as benzaldehyde afterhydrolysis using dilute HCl) was 95%.

Example 3 4-Formylboronic Acid

[0075] A Grignard solution as obtained from Example 1 or 2 was addeddropwise at −50° C. to a suspension of 10.4 g (100 mmol) of trimethylborate in 300 ml of THF over the course of 3 hours. When the additionwas complete, the white suspension was poured into 200 g of ice-water.The suspension was adjusted to pH 1 to 2 using conc. H₂SO₄. When thehydrolysis was complete, the phases were separated, giving 12.45 g (83mmol) of 4-formylboronic acid.

Example 4

[0076] Example 3 was repeated with a reaction temperature of −15° C.:yield 11.85 g (79 mmol) of 4-formylboronic acid.

Example 5 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)benzaldehyde

[0077] A suspension of 5 g (33.3 mmol) of 4-formylphenylboronic acid and3.93 g (33.3 mmol) of pinacol in 25 ml of toluene was refluxed on awater separator. When all the water of reaction had been removed, aclarifying filtration was carried out, and the solvent was removed bydistillation until the product started to crystallize, giving 7.2 g (31mmol) of product.

Example 6 4-Cyanophenylboronic Acid

[0078] 17 g (100 mmol) of hydroxylamine sulfate were added at 70° C. to15 g (100 mmol) of 4-formylphenylboronic acid, 10 g of water, 5 g (60mmol) of pyridine and 200 ml of toluene. The mixture was then refluxedon a water separator. When all the water had been removed, thepyridinium salts were separated off, giving 12.7 g (87%) of4-cyanophenylboronic acid.

Example 7 Pinacolyl 4-cyanophenylboronate

[0079] 17 g (100 mmol) of hydroxylamine sulfate were added at 70° C. to23.2 g (100 mmol) of pinacolyl 4-formylphenylboronate, 10 g of water, 5g (60 mmol) of pyridine and 200 ml of toluene. The mixture was thenrefluxed on a water separator. When all the water had been removed, thepyridinium salts were separated off, giving 20.8 g (91%) of pinacolyl4-cyanophenylboronate.

Example 8 4-Carboxyphenylboronic Acid

[0080] 14.5 g (100 mmol) of 4-cyanophenylboronic acid were dissolved ina mixture of 11 g (200 mmol) of potassium hydroxide and 10 g of water in100 ml of methanol, and the mixture was refluxed until the evolution ofammonia gas was complete, giving 14.9 g (90 mmol) of4-carboxyphenylboronic acid.

Example 9 Esterification of 4-carboxyphenylboronic Acid

[0081] 4-Carboxyphenylboronic acid and an equimolar amount of theappropriate diol shown in Table 1 were refluxed in 200 ml of toluene.When all the water formed had been removed on a water separator (afterabout 1 hour), the solution was filtered through a suction filter whilestill hot. The solvent was subsequently removed by distillation. TABLE 1Amount of starting Diol material Product Yield Pinacol 30 g4-(4,4,5,5-Tetramethyl-  43.1 g (97%) (180 [1,3,2]dioxaborolan-2-yl)-mmol) benzoic acid Neopentyl 16.6 g 4-(5,5-Dimethyl-   22 g (94%) glycol(100 [1,3,2]dioxaborinan-2-yl)- mmol) benzoic acid Ethylene glycol 200 g4-[1,3,2]Dioxaborolan-2-yl- 227.1 g (98%) (1.2 mol) benzoic acidDiethanolamine 20 g 4-[1,3,6,2]Dioxazaborocan-  27.5 g (98%) (1202-yl-benzoic acid mmol)

Example 10 4-Carboxamidophenylboronic Acid

[0082] 10 g (68 mmol) of 4-cyanophenylboronic acid were refluxed for 6hours in a mixture of 12 g (135 mmol) of manganese dioxide, 10 g ofwater and 150 ml of cyclohexane. 9.6 g (58 mmol) of4-carboxamidophenylboronic acid were isolated.

Example 11 4-(Trimethoxymethyl)phenylboronic Acid

[0083] 30 g (203 mmol) of 4-cyanophenylboronic acid were dissolved in200 ml of methanol, and 200 ml of 1 M hydrogen chloride solution indiethyl ether were added. The reaction mixture was refluxed for 8 hours,giving 38.5 g (170 mmol) 4-(trimethoxymethyl)phenylboronic acid

Example 12 4-(Methylamino)phenylboronic Acid

[0084] 30 g (203 mmol) of 4-cyanophenylboronic acid were dissolved in200 ml of tetrahydrofuran, and 0.5 g of Raney nickel were added. Astream of hydrogen was passed through the reaction mixture for 8 hours,giving 29.8 g (199 mmol) of 4-(methylamino)phenylboronic acid.

Example 13 4-(Hydroxymethyl)phenylboronic Acid

[0085] 15 g (100 mmol) of 4-formylphenylboronic acid were dissolved in200 ml of tetrahydrofuran, and 0.25 g of Raney nickel were added. Astream of hydrogen was passed through the reaction mixture for 8 hours,giving 14.8 g (97 mmol) of 4-(hydroxymethyl)phenylboronic acid.

Example 14 Pinacolyl 4-(hydroxymethyl)phenylboronate

[0086] Analogously to Example 12, 12 g (52 mmol) of pinacolyl4-formylphenylboronate were hydrogenated in 100 ml of methanol, giving11.7 g (50 mmol) of 4-(hydroxymethyl)phenylboronic acid.

1. A process for the preparation of a compound of the formula (I)

in which Q¹ and Q² are each OH or together are a divalent radical of theformula (Ib)

Z is —CHO, D, —CH₂Y or X, where D is a protected aldehyde group, Y ishydroxyl or amino, and X is cyano, COOH, COCl, CONH₂ or C(OR)₃, where Ris C₁-C₅-alkyl or phenyl, and where Z is in the ortho-, meta- orpara-position to the boronic acid radical; R¹ to R⁴, independently ofone another, are hydrogen, C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl,C₃-C₁₂-cycloalkyl, (C₁-C₁₂-)-alkoxy, O-phenyl, O-benzyl, aryl,heteroaryl, fluorine, N(alkyl)₂, N[Si(C₁-C₄-alkyl)₃]₂ or CF₃, or R¹ andR², or R³ and R⁴, or R¹ and R², and R³ and R⁴ together form a 5- or6-membered aliphatic or aromatic ring; which comprises a) reacting acompound of the formula (II)

 with magnesium in the presence of i) an anthracene compound and,optionally a transition-metal halide and, optionally, a magnesiumhalide; or ii) a transition-metal halide and, optionally, a magnesiumhalide, where the anthracene compound is a compound from the groupconsisting of anthracene, Mg anthracene, substituted anthracene andsubstituted Mg anthracene, to give an arylmagnesium chloride of theformula (III)

b) reacting the compound of the formula (III) with a borate of theformula B(OR′)₃, in which R′ are identical to or different from oneanother and are straight-chain or branched (C₁-C₈)-alkyl radicals,phenyl radicals which are unsubstituted or substituted by one or two(C₁-C₄)-alkyl groups or (C₁-C₄)-alkoxy groups, and hydrolyzing theproduct to give a compound of the formula (IV)

in which D¹ is CHO or D; Q¹ and Q² are each OH or together are adivalent radical of the formula (IVb)

c) optionally oxidizing the compound of the formula (IV) or (IVb) inwhich D¹ is CHO to give a compound of the formula (I) in which Z is X,or optionally reducing the compound of the formula (IV) or (IVb) to givea compound of the formula (I) in which Z is CH₂Y.
 2. The process asclaimed in claim 1, wherein R¹ to R⁴ are hydrogen, methyl, ethyl,propyl, butyl, methoxy, ethoxy, propoxy, butoxy or fluorine.
 3. Theprocess as claimed in claim 1, wherein D is an acetal of the formula (V)or (VI)

in which R⁵ to R⁸ are identical or different and are hydrogen,C₁-C₁₂-alkyl or phenyl, or R⁶ and R⁷ together form a 5- or 6-memberedaliphatic or aromatic ring; or D is an oxazolidine of the formula (VII)or an oxazoline of the formula (VIII)

in which R⁹ is C₁-C₆-alkyl, phenyl or benzyl, unsubstituted orsubstituted on the aromatic ring.
 4. The process as claimed in claim 1,wherein the borate B(OR′)₃ is trimethyl borate, triethyl borate,tri-n-propyl borate, triisopropyl borate, tri-n-butyl borate andtriisobutyl borate.
 5. The process as claimed in claim 1, wherein stepa) is carried out in the presence of anthracene, Mg anthracene,9,10-diphenylanthracene or Mg 9,10-diphenylanthracene.
 6. The process asclaimed in claim 1, wherein step a) is carried out in the presence ofMgCl₂ or MgBr₂, and in the presence of FeCl₂, MnCl₂, FeBr₂ oder MnBr₂.7. The process as claimed in claim 1, wherein the compound of theformula (IV) is esterified using an alcohol of the formulaHO-(C₁-C₁₂)-alkyl, HO-(C₂-C₁₂)-alkenyl, HO-(C₂-C₁₂)-alkynyl, HO-aryl,HO-alkylaryl, (C₃-C₁₂)-cycloalkane-1,2-diol, cycloalkane-1,2-diol,(C₅-C₁₂)-cycloalkene-1,2-diol, (C₅-C₁₂)-cycloalkane-1,3-diol,(C₅-C₁₂)-cycloalkene-1,3-diol or using an alcohol of the formulae (1) to(6)

in which R₁a to R₈a, independently of one another, are hydrogen,C₁-C₁₂-alkyl, C₁-C₁₂-hydroxyalkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl,C₃-C₁₂-cycloalkyl, (C₁-C₁₂)-alkoxy, O-phenyl, O-benzyl, aryl,heteroaryl, fluorine, chlorine, NH₂, NH(alkyl), N(alkyl)₂,N[Si(C₁-C₄-alkyl)₃]₂ or CF₃, two adjacent radicals R₁a to R₈a togetheroptionally form a 5- or 6-membered aliphatic or aromatic ring, and inwhich n is an integer from 2 to
 12. 8. The process as claimed in claim1, wherein the compound of the formula (I) is esterified using analcohol of the formula HO-(C₁-C₁₂)-alkyl, HO-(C₂-C₁₂)-alkenyl,HO-(C₂-C₁₂)-alkynyl, HO-aryl, HO-alkylaryl,(C₃-C₁₂)-cycloalkane-1,2-diol, cycloalkane-1,2-diol,(C₅-C₁₂)-cycloalkene-1,2-diol, (C₅-C₁₂)-cycloalkane-1,3-diol,(C₅-C₁₂)-cycloalkene-1,3-diol or using an alcohol of the formulae (1) to(6)

in which R₁a to R₈a, independently of one another, are hydrogen,C₁-C₁₂-alkyl, C₁-C₁₂-hydroxyalkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl,C₃-C₁₂-cycloalkyl, (C₁-C₁₂)-alkoxy, O-phenyl, O-benzyl, aryl,heteroaryl, fluorine, chlorine, NH₂, NH(alkyl), N(alkyl)₂,N[Si(C₁-C₄-alkyl)₃]₂ or CF₃, two adjacent radicals R₁a to R₈a togetheroptionally form a 5- or 6-membered aliphatic or aromatic ring, and inwhich n is an integer from 2 to
 12. 9. The process as claimed in claim7, wherein, after the esterification, the aldehyde group is oxidized tothe carboxyl, nitrile or carbonyl chloride group.
 10. The process asclaimed in claim 7, wherein, after the esterification, the aldehydegroup is reduced to the methylamino or hydroxymethyl group.
 11. Anarylmagnesium chloride of the formula (III)

in which R¹ to R⁴, independently of one another, are hydrogen,C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, C₃-C₁₂-cycloalkyl,(C₁-C₁₂-)-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl, fluorine,N(alkyl)₂, N[Si(C₁-C₄-alkyl)₃]₂ or CF₃, or R¹ and R², or R³ and R⁴, orR¹ and R², and R³ and R⁴ together form a 5- or 6-membered aliphatic oraromatic ring, and D is a protected aldehyde group.